Investment in Blood Substitutes: Worth the Effort?

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So, are we there yet? With the recent submissions of two applications for product licensure after more than 30 years of effort, we are close--very close.

- Thomas J. Reid, MD, PhD, FACP, Department of Blood Research, Walter Reed Army Institute of Research

Contents

1. Introduction: Is there a Future for Blood Substitutes?
2. Email from Dr. Hae Won Kim
3. Email from Lelio Mario Sarteschi

  • Please click on images to be linked to their references. All images are referenced.

Is There a Future for Blood Substitutes?

Blood substitutes have the potential of replacing allogeneically transfused blood as a therapy, but will this happen? And if so, Expensive cartoonwhen? These are integral questions that need answers, especially for all those companies pouring their resources into research and production. It remains to be seen whether blood substitutes will be another good idea that simply failed to be embraced by the medical community, either by not living up to standards, or by failure to break through the traditions of medical practice.

In the running for the blood race are two major categories that title themselves blood oxygen carriers: perfluorocarbon emulsions (PFCEs) and hemoglobin based oxygen carriers (HBOCs). Questioned in an email about the topic of blood substitutes, Dr. H. Kim stated that HBOCs seem more promising than PFCs because there is currently an HBOC Phase III clinical trial for use in traumatic hemorrhage. He believes that PFCs are having difficulty establishing their safety and effectiveness. Our other expert Lelio M. Sarteschi, M. D., also believes that HBOCs are winning the race. This may be because PFCs don't seem to have the ability to replace blood, although data suggests they are beneficial because they reduce the need for transfused blood.

With all the research being put into blood substitutes and the production of synthetic blood, it seems as if there is no way these products could possibly fail. However, it is important to note that while the products are created to simulate human blood, they are not in fact human blood. This may seem a simple statement, but it is because of this that FDA approval is hard to get: the products must be able to demonstrate a higher or at least equal efficiency to that of blood, with little or no side effects. And nature is a tough competitor. Many of the blood substitutes in trials still have problems that need to be solved before they will be adequately safe, first and foremost increasing the oxygen carriage and discovering any side effects.

Transfused blood has reached a very high safety level in the United States. The incidence of HIV infected blood has fallen to one in two million. However, there are reasons to continue investigation into alternate therapies. There is now a concern that prions may infect the blood supply and quickly spread, causing an outbreak similar to that of HIV in the past. Also, even though blood may be matched from donor to recipient, their are still medical side effects that take place. Along with blood substitutes comes the possibility to eliminate these side-effects. And there are still occasional deathly clerical errors related to transfused blood. Blood substitutes could eliminate all of these problems. In addition they would have a longer shelf life and could be stored over a higher range of temperatures making them ideal for storage depots in preparation for disaster relief of any kind. Finally, because blood oxygen substitutes are expected to be different from blood by nature, it is expected that after approval of several different types, physicians will be able to choose which characteristics best suit their patients' needs.

Another large factor in whether or not blood substitutes will become widely accepted is the consumer base. Is there a market for synthetic blood products? One market would be the military, which has long sought to add a universally compatible blood equivalent to its repertoire to simplify emergency situations. Another significantly smaller market is the Jehovah's Witnesses, who have become advocates of what they call bloodless surgery. Blood substitutes would be able to equally match their need, especially in the event of traumatic injury, where blood cannot be saved. In addition, a growing number of physicians have come to believe that patients should be able to choose their own treatment, and research indicates that at least eighty percent of patients when questioned, indicate that they would prefer not to have blood transfusions.

After FDA approval, major restrictions in the area of blood substitutes are cost and effectiveness. While cost may be an issue, Dr. Kim remarks that if we wait another ten to twenty years, HBOCs should have become an effective therapy and be approved by the FDA. At that point larger quantities may be produced, and the cost will have been lowered. Also significant is the rising cost of transfused blood. Because screening techniques are becoming more advanced, the cost of screening one unit of transfused blood is also rising. However, assuming HBOCs were licensed, 70 000 kilograms of hemoglobin would be required to replace only twenty percent of the US red cell transfusions in one year, and manufacturing of this large amount of raw materials presents a great challenge. It is estimated that the price of one allogeneic unit of blood lies between 100 to 150 US dollars, whereas HBOC prices are estimated to range between 400 to 800 US dollars. Because of these and other factors there Safe Blood for Africa Foundationis no simple way to predict to what scale blood substitutes will succeed as an industry, even after FDA approval, although doctors seem enthusiastic. Blood substitutes are not however expected to completely replace allogeneic transfusions unless their spectrum of clinical application of blood oxygen carriers is brought closer to the level of allogeneic blood. A current projection estimates that a decrease of allogeneic red cell use of upt twenty percent may occur once some products are FDA approved, and this may pose some economic problems for blood clinics.

Reaching into the unforeseeable future, it is only possible to hope that eventually blood substitutes will be able to cover worldwide shortages, and be cheap and stable enough to be distributed in third world countries where much of the allogeneic supplies are contaminated, or wherever else a need occurs.

Email from Dr. Hae Won Kim

(Ph.D, Director of Surgical Research Miriam Hospital in Providence , RI)

Dear Gabriel,

You are asking some 'big' questions for me to answer in just a few minutes.
There's no short answer to most of these questions...

Q: Do you ever think PFC's will become FDA approved as a "blood substitute" and not just an oxygen therapeutic?
My short answer to the first question may be: it really depends on the specific PFC formulation. Two key requirements for FDA approval are demonstration of safety and effectiveness. The current leading PFC products appear to have difficulty establishing both, especially safety. New generations of PFC's with improved formulations are being developed and tested. Some of these new products may have [a] better chance of eventually winning FDA approval (not as permanent replacement for blood but for a short-term application such as traumatic hemorrhagic shock resuscitation when blood is not available).

Q: Do PFC's or artificial hemoglobin seem more promising? Why?
They both appear to be promising in some applications. At the moment a HBOC seems to be leading in the regulatory race for use in traumatic hemorrhage when blood is not available ( Northfield is currently conducting pivotal Phase III clinical trial).

Q: Do you think PFC's will catch on for uses other than "blood substitutes"
(i.e. tumor therapy)?

Yes. Both PFBOCs and HBOCs have potential non-blood substitute applications such as tumor imaging (with brominated PFCs), hypoxic tumor therapy (enhances effectiveness of radiation/chemotherapy when more oxygen is supplied to tumor tissue), tissue/organ perfusate during surgery (e.g., coronary artery/cardiopulmonary bypass), hemodiluent for surgical procedures (to avoid allogeneic blood transfusion), etc.

Q: A major barrier for blood substitutes is FDA approval, which demands survival benefits over existing therapeutic solutions. What are the appropriate markers to measure efficacy within a clinical trial? Mortality?
This is a tough question. As you pointed out, there is no clearly established standard criteria for efficacy of blood substitutes. Although there are some guidelines (FDA issued two Points to Consider documents and recently a Draft Guidance to be released soon). Therefore, appropriate endpoints will have to be defined more or less in the study design considering a proposed specific indication (intended use). It requires a well thought out study that would likely show either improved outcome (e.g., lower mortality, higher rate of transfusion avoidance and/or improved organ functions) or at least non-inferiority (equivalency) to existing therapy. Because of complexity, it is generally necessary to consult FDA regarding appropriateness of the study design and what criteria for endpoints to be used.    

Q: Efforts to create modified hemoglobin through recombinant technology has proven unsuccessful due to high cost. In particular scaling the production of recombinant hemoglobin to meet the anticipated demands is a challenge. What is the prospect of recombinant hemoglobin as being a viable therapeutic solution?
With technological advances in the recombinant technology, rHb will be produced in larger quantities at less cost in the future. I would say that the prospect of one or more rHb-based HBOCs becoming a therapeutic reality in the next 10-20 years is pretty good (for a new drug, it generally takes 10 or more years to secure FDA approval after successfully completion of all the required preclinical and clinical tests).

Email from Lelio Mario Sarteschi

(M.D. of University of Pisa , Department of General Surgery and Transplantation.)

Q: Do you think blood substitutes will ever be in widespread use?  
Yes I do. I think that currently the main question about blood transfusions is their real efficacy on oxygen delivery to tissues. Many recent works emphasized that old banked blood gets worse along the time of conservation. I think oxygen carriers will have a widespread use as soon as this information becomes of common knowledge.

Q: When do you think blood substitutes will be in widespread use?
It all depends on overcoming of uncertainty about adverse effects of current oxygen carriers (i.e. hypertensive effect).

Q: What are the primary applications that these substitutes would be used for?
Mainly in civilian or military trauma settings. After that the oxygen carriers will be very useful to make "augmented" hemodilution. Another field of utilization will be the care of patients refusing blood and blood components and in cases of inadequate supply or patient incompatibility.

Q: Do you think blood substitutes would provide enough benefit to warrant
the trials?
Yes, of course! Besides the doubts about efficacy of blood, we have a lot of literature about the concerns for the harmful effects of transfusions.

Q: Do PFC's or artificial hemoglobin seem more promising?  Why?
Only artificial haemoglobin is very promising. The HBOC have a sigmoid physiologic dissociation curve, whereas PFC emulsions have a linear relationship between O2 partial pressure and O2 content, so high O2 partial pressures are necessary to maximize O2 transport by PFC emulsions. Furthermore the saturation of reticuloendothelial system that occurs with PFCs constrain us to utilize low dosages, whereas we can give HBOCs without limits. Moreover, long-term effects of PFCs are questionable.

Q: If blood substitutes caught on, do you think it would be cheap enough for
everyone to use, or would it only be for the financially sound?
I think it all depends on the law of supply and demand. With the increasing of the demand, the prices of products will be ever more decreasing and so it will be cheap enough for everyone.

Q: Do you ever think PFC's will become FDA approved as a "blood substitute"?
I think no. Nowadays the function of PFCs for achieving a extreme hemodilution can be safely replaced by hyperoxic oxygenation.

Q: What are the major hurdles that Bloodless surgery must overcome before
it is in widespread use?
1) The need for teams that work well together.
2) The willingness to spend more time and attention in care of the patients.
3) The concern about more expensive therapies.
4) The growing conviction that today blood is safer than ever.
5) Perhaps the thought that bloodless surgery is only an alternative therapy for Jehovah's Witnesses.

Learn more about "Bloodless Medicine Research": a website run by Lelio Mario Sarteschi and his colleagues.

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